Combination

ABSTRACT

The present invention relates to a combination, especially a pharmaceutical composition, comprising as active ingredients 
         (i) an AT 1 -receptor antagonist or a pharmaceutically acceptable salt thereof; (ii) (a) an insulin secretion enhancer or a pharmaceutically acceptable salt thereof or (b) an insulin sensitizer or a pharmaceutically acceptable salt thereof; and, in case of a pharmaceutical composition, a pharmaceutically acceptable carrier.

The present invention relates to a combination, especially apharmaceutical composition, comprising as active ingredients

-   -   (i) an AT₁-receptor antagonist or a pharmaceutically acceptable        salt thereof;    -   (ii) (a) an insulin secretion enhancer or a pharmaceutically        acceptable salt thereof or (b) an insulin sensitizer or a        pharmaceutically acceptable salt thereof; and,        in case of a pharmaceutical composition, a pharmaceutically        acceptable carrier.

AT₁-receptor antagonists (also called angiotensin II receptorantagonists or blockers) are understood to be those active ingredientsthat bind to the AT₁-receptor subtype of angiotensin II receptor but donot result in activation of the receptor. As a consequence of theblockade of the AT₁ receptor, these antagonists can, for example, beemployed as antihypertensives or for treating congestive heart failure.

The class of AT₁ receptor antagonists comprises compounds havingdiffering structural features, essentially preferred are thenon-peptidic ones. For example, mention may be made of the compoundsthat are selected from the group consisting of valsartan (cf. EP443983), losartan (cf. EP 253310), candesartan (cf. EP 459136),eprosartan (cf. EP403159), irbesartan (cf. EP 454511), olmesartan (cf.U.S. Pat. No. 5,616,599), tasosartan (cf. EP 539086), and telmisartan(cf. EP 502314), or, in each case, a pharmaceutically acceptable saltthereof.

Preferred AT₁-receptor antagonist are those agents that have beenmarketed, most preferred is valsartan or a pharmaceutically acceptablesalt thereof.

Insulin secretion enhancers are active ingredients that have theproperty to promote the secretion of insulin from pancreatic β-cells.Examples of insulin secretion enhancers are sulfonylureas (SU),especially those which promote the secretion of insulin from pancreaticβ-cells by transmitting signals of insulin secretion via SU receptors inthe cell membrane, Including (but are not limited to) tolbutamide;chlorpropamide; tolazamide; acetohexamide;4-chloro-N-[(1-pyrolidinylamino)carbonyl]-benzensulfonamide(glycopyramide); glibenclamide (glyburide); gliclazide;1-butyl-3-metanilylurea; carbutamide; glibonuride; glipizide;gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide;glymidine; glypinamide; phenbutamide; and tolylcyclamide, or apharmaceutically acceptable salt thereof.

Insulin secretion enhancers furthermore include short-acting insulinsecretion enhancers, such as the new phenylalanine derivativenateglinide [N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine](cf. EP 196222 and EP 526171) of the formula

repaglinide[(S)-2-ethoxy-4-[2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl)benzoicacid—cf. EP 589874]; calcium(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinlycarbonyl)-propionatedihydrate (mitiglinide—cf. EP 507534); furthermore representatives ofthe new generation of SUs such as glimepiride (cf. EP 31058); and infree or pharmaceutically acceptable salt form.

Insulin secretion enhancers likewise include the long-acting insulinsecretion enhancer DPP-IV inhibitors, GLP1 and GLP1 agonists.

DPP-IV is responsible for Inactivating GLP-1. More particularly, DPP-IVgenerates a GLP-1 receptor antagonist and thereby shortens thephysiological response to GLP-1. GLP-1 is a major stimulator ofpancreatic insulin secretion and has direct beneficial effects onglucose disposal.

The DPP-IV Inhibitor can be peptidic or, preferably, non-peptidic.DPP-IV inhibitors are in each case generically and specificallydisclosed e.g. in WO 98/19998, DE 196 16 486 A1, WO 00/34241 and WO95/15309, in each case in particular in the compound claims and thefinal products of the working examples, the subject-matter of the finalproducts, the pharmaceutical preparations and the claims are herebyincorporated into the present application by reference to thesepublications. Preferred are those compounds that are specificallydisclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241,respectively.

GLP-1 is a insulinotropic proteine which was described, e.g., by W. E.Schmidt et al. in Diabetologia 28, 1985, 704-707 and in U.S. Pat. No.5,705,483.

The term “GLP-1 agonists” used herein means variants and analogs ofGLP-1 (7-36)NH₂ which are disclosed in particular in U.S. Pat. No.5,120,712, U.S. Pat. No. 5,118,666, U.S. Pat. No. 5,512,549, WO 91/11457and by C. Orskov et al in J. Biol. Chem. 264 (1989) 12826. The term“GLP-1 agonists” comprises especially compounds like GLP-1 (7-37), inwhich compound the carboxy-terminal amide functionality of Arg36 isdisplaced with Gly at the 37th position of the GLP-1 (7-36)NH₂ moleculeand variants and analogs thereof including GLN⁹GLP-1 (7-37),D-GLN⁹-GLP-1 (7-37), acetyl LYS⁹-GLP-1 (7-37), LYS¹⁸-GLP-1 (7-37) and,in particular, GLP-1(7-37)OH, VAL⁸-GLP-1 (7-37), GLY⁸-GLP-1 (7-37),THR⁸-GLP-1 (7-37) and 4-imidazopropionyl-GLP-1. Special preference isalso given to the GLP agonist analog exendin-4, described by Greig et alin Diabetologia 1999, 42, 45-50.

A preferred insulin secretion enhancer is repaglinide, most preferred isnateglinide. The term nateglinide likewise comprises crystalmodifications such as disclosed in EP 0526171 B1 or U.S. Pat. No.5,488,510, respectively, the subject matter of which, especially withrespect to the identification, manufacture and characterization ofcrystal modifications, is herewith incorporated by reference to thisapplication, especially the subject matter of claims 8 to 10 (beingdirected to the H-form crystal modification) as well as thecorresponding references to the B-form crystal modification.

The structure of the active agents identified by generic or tradenamesmay be taken from the actual edition of the standard compendium “TheMerck Index” or from databases, e.g. Patents International (e.g. IMSWorld Publications). The corresponding content thereof is herebyincorporated by reference. Any person skilled in the art is fullyenabled to identify the active agents and, based on these references,likewise enabled to manufacture and test the pharmaceutical indicationsand properties in standard test models, both in vitro and in vivo.

The term “short-acting insulin secretion enhancer” comprisescorresponding agents with a maximum secretion of insulin that isattained within one hour, preferably within 30 minutes, after theadministration of the agent, most preferably within 20 minutes having abiological half-life, T ½, of less than two hours, preferably, 1.5hours. The term long-acting insulin secretion enhancer” comprisescorresponding agents with a maximum secretion of insulin that isattained more than one hour after administration of the agent.

A preferred insulin sensitizer is metformin or a pharmaceuticallyacceptable salt thereof such as the mono-hydrochloride.

Especially preferred is a combination of valsartan or a pharmaceuticallyacceptable salt thereof and nateglinide or a pharmaceutically acceptablesalt thereof.

The corresponding active ingredients or a pharmaceutically acceptablesalts thereof may also be used in form of a solvate, such as a hydrateor including other solvents, used for crystallization.

The compounds to be combined can be present as pharmaceuticallyacceptable salts. If these compounds have, for example, at least onebasic center, they can form acid addition salts. Corresponding acidaddition salts can also be formed having, if desired, an additionallypresent basic center. The compounds having an acid group (for exampleCOOH) can also form salts with bases.

The pharmaceutical activities as effected by administration ofrepresentatives of the class of AT₁-receptor antagonists or insulinsecretion enhancers, respectively, or of the combination of activeagents used according to the present invention can be demonstrated e.g.by using corresponding pharmacological models known In the pertinentart. The person skilled In the pertinent art is fully enabled to selecta relevant animal test model to prove the hereinbefore and hereinafterindicated therapeutic indications and beneficial effects.

To evaluate the antihypertensive activity of the combination accordingto the invention, for example, the methodology as described by LovenbergW: Animal models for hypertension research. Prog. Clin. Biol. Res. 1987,229, 229240 may be applied. For the evaluation that the combinationaccording to the present Invention may be used for the treatment ofcongestive heart failure, for example, the methods as disclosed by SmithH J, Nuttall A: Experimental models of heart failure. Cardiovasc Res1985, 19, 181-186 may be applied. Molecular approaches such astransgenic methods are also described, for example by Luft et al.:Hypertension-induced end-organ damage. “A new transgemic approach for anold problem.” Hypertension 1999, 33, 212-218.

The insulin secretion enhancing properties of the combination accordingto the present invention may be determined by following the methodologyas disclosed, for example, in the publication of T.Ikenoue et al.Biol.Pharm.Bull. 29(4), 354-359 (1997).

The corresponding subject matter of these four references is herewithincorporated by reference in this specification.

Accordingly, the combination according to the present invention may beused,. e.g., for the prevention, delay of progression or treatment ofdiseases and disorders that may be inhibited by the inhibition of AT,receptor, that may be inhibited by the enhancement of insulin secretionand that may be inhibited by insulin sensitization. Especially, thecombination according to the present invention may be used, e.g., forthe prevention, delay of progression or treatment of diseases anddisorders selected from the group consisting of hypertension, congestiveheart failure, diabetes, especially type 2 diabetes mellitus, diabeticretinopathy, macular degeneration, diabetic nephropathy,glomerulosclerosis, chronic renal failure, diabetic neuropathy, syndromeX, premenstrual syndrome, coronary heart disease, angina pectoris,myocardial infarction, stroke, vascular restenosis, hyperglycemia,hyperinsulinaemia, hyperlipidaemia, hypertryglyceridemia, insulinresistance, impaired glucose metabolism, conditions of impaired glucosetolerance (IGT), conditions of impaired fasting plasma glucose, obesity,diabetic retinopathy, macular degeneration, cataracts, diabeticnephropathy, glomerulosclerosis, diabetic neuropathy, erectiledysfunction, premenstrual syndrome, skin and connective tissuedisorders, foot ulcerations and ulcerative colitis, endothelialdysfunction and impaired vascular compliance. Preferably, saidcombination may be used for the treatment of hypertension, especiallyISH, congestive heart failure, endothelial dysfunction, impairedvascular compliance, IGT and type II diabetes mellitus.

A “disease or condition which may be inhibited by the Inhibition of AT₁receptor” as defined in this application comprises, but is not limitedto hypertension, congestive heart failure, diabetes, especially type 2diabetes mellitus, diabetic retinopathy, macular degeneration, diabeticnephropathy, glomerulosclerosis, chronic renal failure, diabeticneuropathy, syndrome X, premenstrual syndrome, coronary heart disease,angina pectoris, myocardial infarction, stroke, vascular restenosis,endothelial dysfunction and the like. A “disease or condition which maybe inhibited by the enhancement of insulin secretion” as defined In thisapplication comprises, but Is not limited to hyperglycemia,hyperinsulinaemia, hyperlipidaemia, hypertryglyceridemia, insulinresistance, impaired glucose metabolism, conditions of impaired glucosetolerance (IGT), conditions of impaired fasting plasma glucose, obesity,diabetic retinopathy, macular degeneration, cataracts, diabeticnephropathy, glomerulosclerosis, diabetic neuropathy, erectiledysfunction, premenstrual syndrome, coronary heart disease,hypertension, angina pectoris, myocardial infarction, stroke, vascularrestenosis, skin and connective tissue disorders, foot ulcerations andulcerative colitis, endothelial dysfunction and impaired vascularcompliance.

A “disease or condition that may be inhibited by insulin sensitization”as defined in this application comprises, but is not limited tohyperglycemia, hyperinsulinaemia, hyperlipidaemia, hypertryglyceridemia,insulin resistance, impaired glucose metabolism, conditions of impairedglucose tolerance (IGT), conditions of Impaired fasting plasma glucose,obesity, diabetic retinopathy, macular degeneration, cataracts, diabeticnephropathy, glomerulosclerosis, diabetic neuropathy, erectiledysfunction, premenstrual syndrome, coronary heart disease,hypertension, angina pectoris, myocardial infarction, stroke, vascularrestenosis, skin and connective tissue disorders, foot ulcerations andulcerative colitis, endothelial dysfunction and impaired vascularcompliance. Hypertension, in connection with a “disease or conditionwhich may be inhibited by the inhibition of AT, receptor”, a “disease orcondition which may be Inhibited by the enhancement of insulinsecretion”, a “disease or condition that may be inhibited by insulinsensitization” includes and is not limited to mild, moderate and severehypertension as defined in Journal of Hypertension 1999, 17:151-183,especially on page 162. Especially preferred is “isolated systolichypertension” (ISH).

Preferably, the jointly therapeutically effective amounts of the activeagents according to the combination of the present invention can beadministered simultaneously or sequentially in any order, e.g.separately or in a fixed combination.

Under certain circumstances, drugs with different mechanisms of actionmay be combined. However, just considering any combination of drugshaving different modes of action but acting in the similar field doesnot necessarily lead to combinations with advantageous effects.

All the more surprising is the experimental finding that the combinedadministration of an AT₁ receptor antagonist and insulin secretionenhancer and/or an insulin sensitizer, or, in each case, apharmaceutically acceptable form thereof, results not only in abeneficial, especially a potentiating or a synergistic, therapeuticeffect. Independent thereof, additional benefits resulting from combinedtreatment can be achieved such as a surprising prolongation of efficacy,a broader variety of therapeutic treatment and surprising beneficialeffects on diseases and conditions associated with diabetes, e.g. lessgain of weight. An additional and preferred aspect of the persentinvention is the prevention, delay of progression or treatment of thecondition of isolated systolic hypertension and impaired vascularcompliance which means decreased vascular elasticity.

The term “potentiation” shall mean an increase of a correspondingpharmacological activity or therapeutical effect, respectively.Potentiation of one component of the combination according to thepresent invention by co-administration of an other component accordingto the present invention means that an effect is being achieved that isgreater than that achieved with one component alone.

The term “synergistic” shall mean that the drugs, when taken together,produce a total joint effect that is greater than the sum of the effectsof each drug when taken alone.

ISH is the most common form of hypertension in people over 50 years. Itis defined as elevated systolic blood pressure (above 140 mm Hg) inconjunction with normal diastolic blood pressure (below 90 mm Hg).Elevated systolic blood pressure is an Independent risk factor forcardiovascular diseases and may lead e.g. to myocardial hypertrophy andheart failure. ISH is furthermore characterized by an increased pulsepressure, defined as the difference between systolic and diastolic bloodpressures. Elevated pulse pressure is being recognized as the type ofhypertension the least likely to be well controlled. A reduction ofelevated systolic blood pressure and correspondingly of pulse pressureis associated with a significant risk reduction in cardiovascular death.It has surprisingly been found that the combination of an AT₁ receptorantagonist and an insulin secretion enhancer or an insulin sensitizerleads to a decrease of ISH and pulse rate, both in hypertensive patientshaving type 2 diabetes mellitus and in hypertensive patient that do nothave type 2 diabetes mellitus.

Furthermore, it has been found that the chronic co-administration ofeither an insulin sensitizer or an insulin secretion enhancer impartsthe beneficial effect on blood vessel morphology and function andresults in a decrease of vascular stiffness and correspondingly in amaintenance and in an improvement of vascular compliance.

Accordingly, it has been found that the addition of an insulinsensitizer and/or an insulin secretion enhancer to that of an AT₁receptor antagonist would potentiate the effect on systolic bloodpressure and further improve vascular stiffness/compliance. Conversely,the proven antihypertensive effects of an AT₁ receptor antagonist onsystolic and diastolic blood pressure may be potentiated by the additionof an insulin sensitizer and/or an insulin secretion enhancer. Thebenefit of these combinations may also extend to an additional orpotentiated effect on endothelial function, and improve vascularfunction and structure in various organs/tissues including the kidney,heart, eye and brain. Through the reduction in glucose levels, ananti-thrombotic and anti-atherosclerotic effect can also bedemonstrated. Reduction of glucose would prevent or minimize theglycosylation of any structural or functional protein within thecardio-renal system. This effect proves to be highly beneficial byevoking an additive or synergistic effect on vascular function/structurewhen administered with an AT₁ receptor antagonist which alone improvescardiovascular function and structure through a distinct mechanism.

Further benefits are that lower doses of the individual drugs to becombined according to the present invention can be used to reduce thedosage, for example, that the dosages need not only often be smaller butare also applied less frequently, or can be used in order to diminishthe incidence of side effects. This is in accordance with the desiresand requirements of the patients to be treated.

For example, it has turned out that the combination according to thepresent invention provides benefit especially in the treatment of modesthypertension or isolated systolic hypertension that is beneficial to alldiabetic patients regardless of their hypertensive status, e.g. reducingthe risk of negative cardiovascular events by two different modes ofaction.

The AT₁ receptor antagonists, especially valsartan, have proven to bealso useful in the treatment of type 2 diabetes mellitus beyond thereduction of blood pressure in for example improving microalbuminuria.At sub-therapeutic doses, with respect to the treatment of hypertension,the combination according to the invention may be merely used for thetreatment of diabetes, especially type 2 diabetes mellitus. In view ofthe reduced dose of the AT₁ receptor antagonist, there is a considerablesafety profile of the combination making it suitable for first linetherapy.

The present invention relates to the use of a combination comprising asactive ingredients

-   -   (i) an AT₁-receptor antagonist or a pharmaceutically acceptable        salt thereof;    -   (ii) (a) an insulin secretion enhancer or a pharmaceutically        acceptable salt thereof or (b) an insulin sensitizer or a        pharmaceutically acceptable salt thereof;        for the manufacture of a medicament for the prevention, delay of        progression or treatment of a disease and disorder which may be        inhibited by the inhibition of AT₁ receptor and by the        enhancement of insulin secretion, for example, for the        prevention, delay of progression or treatment of hypertension,        especially modest hypertension, ISH, congestive heart failure,        endothelial dysfunction, impaired vascular compliance, IGT and        type II diabetes mellitus.

The present invention also relates to a method for the prevention, delayof progression or treatment of a disease and disorder which may beinhibited by the inhibition of AT₁ receptor and/or by the enhancement ofinsulin secretion comprising administering to a warm-blooded animal,including man, in need thereof jointly therapeutically effective amountsof

-   -   (i) an AT₁-receptor antagonist or a pharmaceutically acceptable        salt thereof;    -   (ii) (a) an insulin secretion enhancer or a pharmaceutically        acceptable salt thereof or (b) an insulin sensitizer or a        pharmaceutically acceptable salt thereof.

The pharmaceutical composition according to the present invention asdescribed hereinbefore and hereinafter may be used for simultaneous useor sequential use in any order, for separate use or as a fixedcombination.

The pharmaceutical composition according to the present inventioncomprises a “kit of parts” in the sense that the components can be dosedindependently or by use of different fixed combinations withdistinguished amounts of the components at different time points. Theparts of the “kit of parts” can then e.g. be administered simultaneouslyor chronologically staggered, that is at different time points and withequal or different time Intervals for any part of the “kit of parts”.Preferably, the time intervals are chosen such that the effect on thetreated disease or condition in the combined use of the parts is largerthan the effect that would be obtained by use of only any one of thecomponents. Preferably, there is at least one beneficial effect, e.g. amutual enhancing of the effect of

-   -   (i) an AT₁-receptor antagonist or a pharmaceutically acceptable        salt thereof;    -   (ii) (a) an insulin secretion enhancer or a pharmaceutically        acceptable salt thereof or (b) an insulin sensitizer or a        pharmaceutically acceptable salt thereof;        in particular a potentiation or a synergism, e.g. a more than        additive effect, additional advantageous effects, less side        effects, a combined therapeutical effect in a non-effective        dosage of one or each of the components, especially a        potentiation or a strong synergism.

The invention furthermore relates to a commercial package comprising thecombination according to the present invention together withinstructions for simultaneous, separate or sequential use.

These pharmaceutical preparations are for enteral, such as oral, andalso rectal or parenteral, administration to homeotherms, with thepreparations comprising the pharmacological active compound either aloneor together with customary pharmaceutical auxiliary substances. Forexample, the pharmaceutical preparations consist of from about 0.1% to90%, preferably of from about 1% to about 80%, of the active compound.Pharmaceutical preparations for enteral or parenteral, and also forocular, administration are, for example, in unit dose forms, such ascoated tablets, tablets, capsules or suppositories and also ampoules.These are prepared in a manner that is known per se, for example usingconventional mixing, granulation, coating, solubulizing or lyophilizingprocesses. Thus, pharmaceutical preparations for oral use can beobtained by combining number of main meals the dose regimen are twotimes a day (BID) or three times a day (TID) or four times a day (QID).

The insulin secretion enhancer repaglinde is preferably administered ina dosage range of about 0.01 mg to about 8 mg, more preferred from about0.5 to about 6 mg.

The insulin sensitizer metformin is preferably administered in a dosagerange of about 100 mg to about 1200 mg per dose unit, especially 500 mg,850 mg or 1000 mg. In a low dose combination, metformin is preferablyadministered in a dosage of 125 mg, 250 mg or 500 mg.

FORMULATION EXAMPLE 1

Film-Coated Tablets: Compostion Components Per Unit (mg) StandardsGranulation Valsartan [=active ingredient] 80.00 Microcrystallinecellulose/ 54.00 NF, Ph. Eur Avicel PH 102 Crospovidone 20.00 NF, Ph.Eur Colloidal anhydrous silica/ 0.75 Ph. Eur/ colloidal silicondioxide/Aerosil 200 NF Magnesium stearate 2.5 NF, Ph. Eur BlendingColloidal anhydrous silica/ 0.75 Ph. Eur/ colloidal silicondioxide/Aerosil 200 NF Magnesium stearate 2.00 NF, Ph. Eur CoatingPurified water*⁾ — DIOLACK pale red 00F34899 7.00 Total tablet mass167.00*⁾Removed during processing.

The film-coated tablet is manufactured e.g. as follows:

A mixture of valsartan, microcrystalline cellulose, crospovidone, partof the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile200, silicon dioxide and magnesium stearate is premixed in a diffusionmixer and then sieve through a screnning mill. The resulting mixture isagain pre-mixed In a diffusion mixer, compacted In a roller compacterand then sieve through a screening mill. To the resulting mixture, therest of the colloidal anhydrous silica/colloidal silicondioxide/Aerosile 200 are added and the final blend is made in adiffusion mixer. The whole mixture is compressed in a rotary tablettingmachine and the tabletts are coated with a film by using Diolack palered in a perforated pan.

FORMULATION EXAMPLE 2

Film-Coated Tablets: Compostion Components Per Unit (mg) StandardsGranulation Valsartan [=active ingredient] 160.00 Microcrystallinecellulose/ 108.00 NF, Ph. Eur Avicel PH 102 Crospovidone 40.00 NF, Ph.Eur Colloidal anhydrous silica/ 1.50 Ph. Eur/ colloidal silicondioxide/Aerosil 200 NF Magnesium stearate 5.00 NF, Ph. Eur BlendingColloidal anhydrous silica/ 1.50 Ph. Eur/ colloidal silicondioxide/Aerosil 200 NF Magnesium stearate 4.00 NF, Ph. Eur CoatingOpadry Light Brown 00F33172 10.00 Total tablet mass 330.00

The film-coated tablet is manufactured e.g. as described in FormulationExample 1.

FORMULATION EXAMPLE 3

Film-Coated Tablets: Compostion Components Per Unit (mg) Standards Core:Internal phase Valsartan 40.00 [=active ingredient] Silica, colloidalanhydrous 1.00 Ph. Eur, USP/NF (Colloidal silicon dioxide) [=Glidant]Magnesium stearate 2.00 USP/NF [=Lubricant] Crospovidone 20.00 Ph. Eur[Disintegrant] Microcrystalline cellulose 124.00 USP/NF [=Binding agent]External phase Silica, colloidal anhydrous, 1.00 Ph. Eur, USP/NF(Colloidal silicon dioxide) [=Glidant] Magnesium stearate 2.00 USP/NF[Lubricant] Film coating Opadry ® brown OOF 16711*⁾ 9.40 PurifiedWater**⁾ — Total tablet mass 199.44*⁾The composition of the Opadry ® brown OOF16711 coloring agent istabulated below.**⁾Removed during processing

Opadry® Composition: Approximate Ingredient % Composition Iron oxide,black (C.I. No. 77499, E 172) 0.50 Iron oxide, brown (C.I. No. 77499, E172 0.50 Iron oxide, red (C.I. No. 77491, E 172) 0.50 Iron oxide, yellow(C.I. No. 77492, E 172) 0.50 Macrogolum (Ph. Eur) 4.00 Titanium dioxide(C.I. No. 77891, E 171) 14.00 Hypromellose (Ph. Eur) 80.00

The film-coated tablet is manufactured e.g. as described in FormulationExample 1.

FORMULATION EXAMPLE 4

Capsules: Compostion Per Unit (mg) Components Valsartan [=activeingredient] 80.00 Microcrystalline cellulose 25.10 Crospovidone 13.00Povidone 12.50 Magnesium stearate 1.30 Sodium lauryl sulphate 0.60 ShellIron oxide, red 0.123 (C.I. No. 77491, EC No. E 172) Iron oxide, yellow0.123 (C.I. No. 77492, EC No. E 172) Iron oxide, black 0.245 (C.I. No.77499, EC No. E 172) Titanium dioxide 1.540 Gelatin 74.969 Total tabletmass 209.50

The tablet is manufactured e.g. as follows:

Granulation/Drying

Valsartan and microcrystallin cellulose are spray-granulated in afluidised bed granulator with a granulating solution consisting ofpovidone and sodium lauryl sulphate dissolved in purified water. Thegranulate obtained is dried in a fluidiesd bed dryer.

Milling/Blending

The dried granulate is milled together with crospovidone and magnesiumstearate. The mass is then blended in a conical srew type mixer forapproximately 10 minutes.

Encapsulation

Teh empty hard gelatin capsules are filled with the blended bulkgranules under controlled temperature and humidity conditions. The filedcapsules are dedustee, visually inspected, weightchecked and quarantieduntil by Quality assurance department.

FORMULATION EXAMPLE 5

Capsules: Composition Per Unit (mg) Components Valsartan [=activeingredient] 160.00 Microcrystalline cellulose 50.20 Crospovidone 26.00Povidone 25.00 Magnesium stearate 2.60 Sodium lauryl sulphate 1.20 ShellIron oxide, red 0.123 (C.I. No. 77491, EC No. E 172) Iron oxide, yellow0.123 (C.I. No. 77492, EC No. E 172) Iron oxide, black 0.245 (C.I. No.77499, EC No. E 172) Titanium dioxide 1.540 Gelatin 74.969 Total tabletmass 342.00

The formulation is manufactured e.g. as described in Formulation Example4.

FORMULATION EXAMPLE 6

Hard Gelatine Capsule: Composition Components Per Unit (mg) Valsartan[=active ingredient] 80.00 Sodium laurylsulphate 0.60 Magnesium stearate1.30 Povidone 12.50 Crospovidone 13.00 Microcrystalline cellulose 21.10Total tablet mass 130.00

EXAMPLES 7 to 11

Example 7 8 9 10 11 Composition Composition Composition CompositionComposition per per per per Components per unit (mg) unit (mg) unit (mg)unit (mg) unit (mg) Granulation Valsartan 80.000 160.000 40.000 320.000320.000 Drug Substance (DS) Microcrystalline 54.000 108.000 27.000216.000 216.000 Cellulose (NF, Ph.Eur.)/ Avicel PH 102 Crospovidone (NF,15.000 30.000 7.500 80.000 60.000 Ph.Eur.) Colloidal Anhydrous 1.5003.000 0.750 3.000 6.000 Silica (Ph. Eur.)/Colloidal Silicon Dioxide(NF)/Aerosil 200 Magnesium Stearate 3.000 6.000 1.500 10.000 12.000 (NF,Ph.Eur.) Blending Colloidal Anhydrous — — — 3.000 — Silica (Ph.Eur.)/Colloidal Silicon Dioxide (NF)/Aerosil 200 Magnesium Stearate,1.500 3.000 0.750 8.000 6.000 NF, Ph.Eur. Core Weight/mg 155.000 310.00077.500 640.000 620.000 Coating — — 3.800 15.000 16.000

EXAMPLE 12

108,000 tablets, each which contain 120 mg of nateglinide are preparedas follows: Composition: nateglinide 12.960 kg  lactose, NF 30.564 kg microcrystalline cellulose, NF 15.336 kg  povidone, USP 2.592 kgcroscarmellose sodium, NF 3.974 kg colloidal silicon dioxide, NF 1.382kg magnesium stearate, NF 1.231 kg coating: opadiy yellow 1.944 kgpurified water, USP* Q.S.*removed during process

Preparation process: The microcrystalline cellulose, povidone, part ofthe croscarmellose sodium, nateglinide and lactose are mixed in a highshear mixer and afterwards granulated using purified water.Alternatively, the microcrystalline cellulose, povidone, a portion ofthe croscarmellose sodium, nateglinide and lactose are granulated in acollette gral granulator with the addition of purified water. The wetgranules are dried in a fluid bed dryer and passed through a screen. Thecolloidal silicon dioxide and the rest of the croscarmellose sodium aremixed, passed through a screen and blended with the dried granules in aV-blender. The magnesium stearate Is passed through a screen, blendedwith the blend from the V-blender and afterwards the total mixture iscompressed to tablets. The opadry yellow is suspended in purified waterand the tablets are coated with the coating suspension.

EXAMPLES 13-15

Component 60 mg 120 mg 180 mg Starlix DS (H-form crystal modification)  60  120 180 Lactose Monohydrate  141.5  283  214MicrocrystallineCellulose   71  142  107 Povidone K30   12   24   23Croscarmellose Sodium   12   24   34 Sub-Total (Granulation)  296.5  593 558 Croscarmellose Sodium   6.4   12.8   24.5 Colloidal SiliconeDioxide   6.4   12.8   12.3 Magnesium Stearate   5.7   11.4   15.2Sub-Total (Core) (315) (630) (610) Opadry   9   18   18 Total  324  648 628

1. A pharmaceutical composition, wherein the active ingredients consistof (i) an AT₁-receptor antagonist or a pharmaceutically acceptable saltthereof; (ii) (a) an insulin secretion enhancer or a pharmaceuticallyacceptable salt thereof or (b) an insulin sensitizer or apharmaceutically acceptable salt thereof; and (iii) a pharmaceuticallyacceptable carrier.
 2. A compostion acording to claim 1 wherein the AT₁receptor antagonist is selected from the group consisting of valsartan,losartan, candesartan, eprosartan, irbesartan, olmesartan, tasosartan,and telmisartan, and, in each case, a pharmaceutically acceptable saltthereof.
 3. A composition according to claim 2 wherein the AT₁ receptorantagonist is valsartan or a pharmaceutically acceptable salt thereof.4. A composition according to claim 1 wherein the insulin secretionenhancer is selected from tolbutamide; chlorpropamide; tolazamide;acetohexamide; glycopyramide; glibenclamide; gliclazide;1-butyl-3-metanilylurea; carbutamide; glibonuride; glipizide;gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide;glymidine; glypinamide; phenbutamide; tolylcyclamide, nategliniderepaglinide; mitiglinide; glimepiride; and, in each case, apharmaceutically acceptable salt thereof.
 5. A composition according toclaim 4 wherein the insulin secretion enhancer is nateglinide or apharmaceutically acceptable salt thereof.
 6. A composition according toclaim 1 wherein the insulin sensitizer is metformin or apharmaceutically acceptable salt thereof.
 7. A composition according toclaim 1 for the prevention, delay of progression or treatment of a ofdisease or disorder selected from the group consisting of hypertension,congestive heart failure, diabetes, especially type 2 diabetes mellitus,diabetic retinopathy, macular degeneration, diabetic nephropathy,glomerulosclerosis, chronic renal failure, diabetic neuropathy, syndromeX, premenstrual syndrome, coronary heart disease, angina pectoris,myocardial infarction, stroke, vascular restenosis, hyperglycemia,hyperinsulinaemia, hyperlipidaemia, hypertryglyceridemia, insulinresistance, impaired glucose metabolism, conditions of impaired glucosetolerance (IGT), conditions of impaired fasting plasma glucose, obesity,diabetic retinopathy, macular degeneration, cataracts, diabeticnephropathy, glomerulosclerosis, diabetic neuropathy, erectiledysfunction, skin and connective tissue disorders, foot ulcerations andulcerative colitis, endothelial dysfunction and impaired vascularcompliance.
 8. A composition according to claim 1 for the prevention,delay of progression or treatment of a of disease or disorder selectedfrom the group consisting of hypertension, especially ISH, congestiveheart failure, endothelial dysfunction, impaired vascular compliance,IGT and type II diabetes mellitus.
 9. A method for the prevention, delayof progression or treatment of a disease or disorder which may beinhibited by the inhibition of AT₁ receptor and/or by the enhancement ofinsulin secretion comprising administering to a warm-blooded animal,including man, in need thereof jointly therapeutically effective amountsof (i) an AT₁-receptor antagonist or a pharmaceutically acceptable saltthereof; (ii) (a) an insulin secretion enhancer or a pharmaceuticallyacceptable salt thereof or (b) an insulin sensitizer or apharmaceutically acceptable salt thereof.
 10. Use of a combinationcomprising as active ingredients (i) an AT₁-receptor antagonist or apharmaceutically acceptable salt thereof; (ii) (a) an insulin secretionenhancer or a pharmaceutically acceptable salt thereof or (b) an insulinsensitizer or a pharmaceutically acceptable salt thereof; for themanufacture of a medicament for the prevention, delay of progression ortreatment of a disease or disorder which may be inhibited by theinhibition of AT₁ receptor and by the enhancement of insulin secretion.11. The composition according to claim 2 for the prevention, delay ofprogression or treatment of a of disease or disorder selected from thegroup consisting of hypertension, congestive heart failure, diabetes,especially type 2 diabetes mellitus, diabetic retinopathy, maculardegeneration, diabetic nephropathy, glomerulosclerosis, chronic renalfailure, diabetic neuropathy, syndrome X, premenstrual syndrome,coronary heart disease, angina pectoris, myocardial infarction, stroke,vascular restenosis, hyperglycemia, hyperinsulinaemia, hyperlipidaemia,hypertryglyceridemia, insulin resistance, impaired glucose metabolism,conditions of impaired glucose tolerance (IGT), conditions of impairedfasting plasma glucose, obesity, diabetic retinopathy, maculardegeneration, cataracts, diabetic nephropathy, glomerulosclerosis,diabetic neuropathy, erectile dysfunction, skin and connective tissuedisorders, foot ulcerations and ulcerative colitis, endothelialdysfunction and impaired vascular compliance.
 12. The compositionaccording to claim 3 for the prevention, delay of progression ortreatment of a of disease or disorder selected from the group consistingof hypertension, congestive heart failure, diabetes, especially type 2diabetes mellitus, diabetic retinopathy, macular degeneration, diabeticnephropathy, glomerulosclerosis, chronic renal failure, diabeticneuropathy, syndrome X, premenstrual syndrome, coronary heart disease,angina pectoris, myocardial infarction, stroke, vascular restenosis,hyperglycemia, hyperinsulinaemia, hyperlipidaemia, hypertryglyceridemia,insulin resistance, impaired glucose metabolism, conditions of impairedglucose tolerance (IGT), conditions of impaired fasting plasma glucose,obesity, diabetic retinopathy, macular degeneration, cataracts, diabeticnephropathy, glomerulosclerosis, diabetic neuropathy, erectiledysfunction, skin and connective tissue disorders, foot ulcerations andulcerative colitis, endothelial dysfunction and impaired vascularcompliance.
 13. The composition according to claim 4 for the prevention,delay of progression or treatment of a of disease or disorder selectedfrom the group consisting of hypertension, congestive heart failure,diabetes, especially type 2 diabetes mellitus, diabetic retinopathy,macular degeneration, diabetic nephropathy, glomerulosclerosis, chronicrenal failure, diabetic neuropathy, syndrome X, premenstrual syndrome,coronary heart disease, angina pectoris, myocardial infarction, stroke,vascular restenosis, hyperglycemia, hyperinsulinaemia, hyperlipidaemia,hypertryglyceridemia, insulin resistance, impaired glucose metabolism,conditions of impaired glucose tolerance (IGT), conditions of impairedfasting plasma glucose, obesity, diabetic retinopathy, maculardegeneration, cataracts, diabetic nephropathy, glomerulosclerosis,diabetic neuropathy, erectile dysfunction, skin and connective tissuedisorders, foot ulcerations and ulcerative colitis, endothelialdysfunction and impaired vascular compliance.
 14. The compositionaccording to claim 5 for the prevention, delay of progression ortreatment of a of disease or disorder selected from the group consistingof hypertension, congestive heart failure, diabetes, especially type 2diabetes mellitus, diabetic retinopathy, macular degeneration, diabeticnephropathy, glomerulosclerosis, chronic renal failure, diabeticneuropathy, syndrome X, premenstrual syndrome, coronary heart disease,angina pectoris, myocardial infarction, stroke, vascular restenosis,hyperglycemia, hyperinsulinaemia, hyperlipidaemia, hypertryglyceridemia,insulin resistance, impaired glucose metabolism, conditions of impairedglucose tolerance (IGT), conditions of impaired fasting plasma glucose,obesity, diabetic retinopathy, macular degeneration, cataracts, diabeticnephropathy, glomerulosclerosis, diabetic neuropathy, erectiledysfunction, skin and connective tissue disorders, foot ulcerations andulcerative colitis, endothelial dysfunction and impaired vascularcompliance.
 15. The composition according to claim 6 for the prevention,delay of progression or treatment of a of disease or disorder selectedfrom the group consisting of hypertension, congestive heart failure,diabetes, especially type 2 diabetes mellitus, diabetic retinopathy,macular degeneration, diabetic nephropathy, glomerulosclerosis, chronicrenal failure, diabetic neuropathy, syndrome X, premenstrual syndrome,coronary heart disease, angina pectoris, myocardial infarction, stroke,vascular restenosis, hyperglycemia, hyperinsulinaemia, hyperlipidaemia,hypertryglyceridemia, insulin resistance, impaired glucose metabolism,conditions of impaired glucose tolerance (IGT), conditions of impairedfasting plasma glucose, obesity, diabetic retinopathy, maculardegeneration, cataracts, diabetic nephropathy, glomerulosclerosis,diabetic neuropathy, erectile dysfunction, skin and connective tissuedisorders, foot ulcerations and ulcerative colitis, endothelialdysfunction and impaired vascular compliance.
 16. The compositionaccording to claim 2 for the prevention, delay of progression ortreatment of a of disease or disorder selected from the group consistingof hypertension, especially ISH, congestive heart failure, endothelialdysfunction, impaired vascular compliance, IGT and type II diabetesmellitus.
 17. The composition according to claim 3 for the prevention,delay of progression or treatment of a disease or disorder selected fromthe group consisting of hypertension, especially ISH, congestive heartfailure, endothelial dysfunction, impaired vascular compliance, IGT andtype II diabetes mellitus.
 18. The composition according to claim 4 forthe prevention, delay of progression or treatment of a disease ordisorder selected from the group consisting of hypertension, especiallyISH, congestive heart failure, endothelial dysfunction, impairedvascular compliance, IGT and type II diabetes mellitus.
 19. Thecomposition according to claim 5 for the prevention, delay ofprogression or treatment of a disease or disorder selected from thegroup consisting of hypertension, especially ISH, congestive heartfailure, endothelial dysfunction, impaired vascular compliance, IGT andtype II diabetes mellitus.
 20. The composition according to claim 6 forthe prevention, delay of progression or treatment of a of disease ordisorder selected from the group consisting of hypertension, especiallyISH, congestive heart failure, endothelial dysfunction, impairedvascular compliance, IGT and type II diabetes mellitus.
 21. Thecomposition according to claim 7 for the prevention, delay ofprogression or treatment of a disease or disorder selected from thegroup consisting of hypertension, especially ISH, congestive heartfailure, endothelial dysfunction, impaired vascular compliance, IGT andtype II diabetes mellitus.